HIT CF and CHOICES: a study investigating a new triple combination CFTR modulator therapy based on organoid responsiveness in people with CF who have rare CFTR gene mutations

The HIT-CF team shared the results from this study in October 2025. This study had two parts. 

Part 1 was a lab study looking at how well this new triple modulator therapy worked in organoids (‘mini-organs’ grown from cells from people with CF). The ‘mini-organs’ were tested using a lab test called a forskolin induced swelling (FIS) test to check if and how well the treated CFTR protein was working. More than 500 people were recruited to part 1 of the study. 

Part 2 was a clinical trial looking at how well this treatment worked in people with CF. Over 40 people with diverse CFTR variants were involved in part 2, including people with very rare variants. The results showed a wide range of change in lung function (of up to 22% increase in predicted FEV1), along with matching changes in sweat chloride levels and patient-reported symptoms. 

Importantly, the lab results matched the clinical trial results. These findings therefore strongly support the FIS test as a reliable way of measuring how well the CFTR protein works and how this changes in response to possible treatments. This means FIS tests can be used to help pre-select people for clinical trials and identify or predict who is likely to respond to certain modulators based on their organoid results. 

This is particularly important because people with rare CFTR variants are often not invited to take part in clinical trials. Being able to predict who might benefit from a possible treatment could mean that people with rare CFTR variants are able to take part in more trials that could benefit them. 

The study also shows that this new triple modulator combination therapy may be a promising first line treatment for people who have positive results in the FIS test.

You can find the full results here: https://doi.org/10.1016/j.jcf.2025.10.007